Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer

被引：645

作者：

Lastwika, Kristin J. ^{[1
,2
]}

Wilson, Willie, III ^{[3
]}

Li, Qing Kay ^{[4
]}

Norris, Jeffrey ^{[1
]}

Xu, Haiying ^{[5
]}

Ghazarian, Sharon R. ^{[6
]}

Kitagawa, Hiroshi ^{[1
]}

Kawabata, Shigeru ^{[1
]}

Taube, Janis M. ^{[5
]}

Yao, Sheng ^{[7
]}

Liu, Linda N. ^{[7
]}

Gills, Joell J. ^{[1
]}

Dennis, Phillip A. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA

[2] George Washington Univ, Inst Biomed Sci, Washington, DC USA

[3] NIH, Canc Biol & Genet Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA

[4] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA

[5] Johns Hopkins Univ, Dept Dermatol, Baltimore, MD 21218 USA

[6] Johns Hopkins Univ, Biostat Epidemiol & Data Management Core, Baltimore, MD USA

[7] Amplimmune Inc, Gaithersburg, MD USA

来源：

CANCER RESEARCH | 2016年 / 76卷 / 02期

关键词：

ANTI-PD-L1; ANTIBODY; LIGAND-1; EXPRESSION; B7-H1; GENE-EXPRESSION; UP-REGULATION; T-CELLS; PHASE-I; KINASE; SAFETY; IMMUNORESISTANCE;

D O I：

10.1158/0008-5472.CAN-14-3362

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT-mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNg-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT-mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where anmTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells. (C) 2015 AACR.

引用

页码：227 / 238

页数：12

共 51 条

[1] Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors [J].

Akbay, Esra A. ;

Koyama, Shohei ;

Carretero, Julian ;

Altabef, Abigail ;

Tchaicha, Jeremy H. ;

Christensen, Camilla L. ;

Mikse, Oliver R. ;

Cherniack, Andrew D. ;

Beauchamp, Ellen M. ;

Pugh, Trevor J. ;

Wilkerson, Matthew D. ;

Fecci, Peter E. ;

Butaney, Mohit ;

Reibel, Jacob B. ;

Soucheray, Margaret ;

Cohoon, Travis J. ;

Janne, Pasi A. ;

Meyerson, Matthew ;

Hayes, D. Neil ;

Shapiro, Geoffrey I. ;

Shimamura, Takeshi ;

Sholl, Lynette M. ;

Rodig, Scott J. ;

Freeman, Gordon J. ;

Hammerman, Peter S. ;

Dranoff, Glenn ;

Wong, Kwok-Kin .

CANCER DISCOVERY, 2013, 3 (12) :1355-1363

[2] Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis [J].

Bissler, John J. ;

McCormack, Francis X. ;

Young, Lisa R. ;

Elwing, Jean M. ;

Chuck, Gail ;

Leonard, Jennifer M. ;

Schmithorst, Vincent J. ;

Laor, Tal ;

Brody, Alan S. ;

Bean, Judy ;

Salisbury, Shelia ;

Franz, David N. .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (02) :140-151

[3] Tumor B7-H1 and B7-H3 Expression in Squamous Cell Carcinoma of the Lung [J].

Boland, Jennifer M. ;

Kwon, Eugene D. ;

Harrington, Susan M. ;

Wampfler, Jason A. ;

Tang, Hui ;

Yang, Ping ;

Aubry, Marie Christine .

CLINICAL LUNG CANCER, 2013, 14 (02) :157-163

[4] Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer [J].

Brahmer, Julie R. ;

Tykodi, Scott S. ;

Chow, Laura Q. M. ;

Hwu, Wen-Jen ;

Topalian, Suzanne L. ;

Hwu, Patrick ;

Drake, Charles G. ;

Camacho, Luis H. ;

Kauh, John ;

Odunsi, Kunle ;

Pitot, Henry C. ;

Hamid, Omid ;

Bhatia, Shailender ;

Martins, Renato ;

Eaton, Keith ;

Chen, Shuming ;

Salay, Theresa M. ;

Alaparthy, Suresh ;

Grosso, Joseph F. ;

Korman, Alan J. ;

Parker, Susan M. ;

Agrawal, Shruti ;

Goldberg, Stacie M. ;

Pardoll, Drew M. ;

Gupta, Ashok ;

Wigginton, Jon M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (26) :2455-2465

[5] T-helper-1-cell cytokines drive cancer into senescence [J].

Braumueller, Heidi ;

Wieder, Thomas ;

Brenner, Ellen ;

Assmann, Sonja ;

Hahn, Matthias ;

Alkhaled, Mohammed ;

Schilbach, Karin ;

Essmann, Frank ;

Kneilling, Manfred ;

Griessinger, Christoph ;

Ranta, Felicia ;

Ullrich, Susanne ;

Mocikat, Ralph ;

Braungart, Kilian ;

Mehra, Tarun ;

Fehrenbacher, Birgit ;

Berdel, Julia ;

Niessner, Heike ;

Meier, Friedegund ;

van den Broek, Maries ;

Haering, Hans-Ulrich ;

Handgretinger, Rupert ;

Quintanilla-Martinez, Leticia ;

Fend, Falko ;

Pesic, Marina ;

Bauer, Juergen ;

Zender, Lars ;

Schaller, Martin ;

Schulze-Osthoff, Klaus ;

Roecken, Martin .

NATURE, 2013, 494 (7437) :361-365

[6] Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses [J].

Butte, Manish J. ;

Keir, Mary E. ;

Phamduy, Theresa B. ;

Sharpe, Arlene H. ;

Freeman, Gordon J. .

IMMUNITY, 2007, 27 (01) :111-122

[7]

Chen YB, 2012, TUMORI, V98, P751, DOI 10.1700/1217.13499

[8] PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer [J].

Crane, C. A. ;

Panner, A. ;

Murray, J. C. ;

Wilson, S. P. ;

Xu, H. ;

Chen, L. ;

Simko, J. P. ;

Waldman, F. M. ;

Pieper, R. O. ;

Parsa, A. T. .

ONCOGENE, 2009, 28 (02) :306-312

[9] Update on Immune Checkpoint Inhibitors in Lung Cancer [J].

Creelan, Benjamin C. .

CANCER CONTROL, 2014, 21 (01) :80-89

[10] PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients [J].

D'Incecco, A. ;

Andreozzi, M. ;

Ludovini, V. ;

Rossi, E. ;

Capodanno, A. ;

Landi, L. ;

Tibaldi, C. ;

Minuti, G. ;

Salvini, J. ;

Coppi, E. ;

Chella, A. ;

Fontanini, G. ;

Filice, M. E. ;

Tornillo, L. ;

Incensati, R. M. ;

Sani, S. ;

Crino, L. ;

Terracciano, L. ;

Cappuzzo, F. .

BRITISH JOURNAL OF CANCER, 2015, 112 (01) :95-102

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